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Structural changes by sulfoxidation of phenothiazine drugs

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Summary

The side-chain conformations of psychoactive phenothiazine drugs in crystals are different from those of biologically inactive ring sulfoxide metabolites. This study examines the potential energies, molecular conformations and electrostatic potentials in chlorpromazine, levomepromazine (methotrimeprazine), their sulfoxide metabolites and methoxypromazine. The purpose of the study was to examine the significance of the different crystal conformations of active and inactive phenothiazine derivatives, and to determine why phenothiazine drugs lose most of their biological activity by sulfoxidation. Quantum mechanics and molecular mechanics calculations demonstrated that conformations with the side chain folded over the ring structure had lowest potential energy in vacuo, both in the drugs and in the sulfoxide metabolites. In the sulfoxides, side chain conformations corresponding to the crystal structure of chlorpromazine sulfoxide were characterized by stronger negative electrostatic potentials around the ring system than in the parent drugs. This may weaken the electrostatic interaction of sulfoxide metabolites with negatively charged domains in dopamine receptors, and cause the sulfoxides to be virtually inactive in dopamine receptor binding and related pharmacological tests.

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Author notes

  1. Shashidhar N. Rao

    Present address: Drug Design, Searle Research and Development, 4901 Searle Parkway, 60077, Skokie, IL, U.S.A.

Authors and Affiliations

  1. Department of Pharmacology, Institute of Medical Biology, University of Tromsø, N-9001, Tromsø, Norway

    Svein G. Dahl

  2. Department of Pharmaceutical Chemistry, University of California, 94143, San Francisco, CA, U.S.A.

    Svein G. Dahl, Peter A. Kollman, Shashidhar N. Rao & U. Chandra Singh

Authors
  1. Svein G. Dahl
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  2. Peter A. Kollman
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  3. Shashidhar N. Rao
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  4. U. Chandra Singh
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Dahl, S.G., Kollman, P.A., Rao, S.N. et al. Structural changes by sulfoxidation of phenothiazine drugs. J Computer-Aided Mol Des 6, 207–222 (1992). https://doi.org/10.1007/BF00123377

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  • DOI: https://doi.org/10.1007/BF00123377

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